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Such therapy is often sub\u2010optimal, however, particularly in patients with reduced LDL receptors (familial hypercholesterolemia), and novel or adjuvant therapies are therefore warranted. Cholesterol elimination is profoundly influenced by the rate of its conversion to bile acids (BA), regulated by the enzyme Cyp7a1. Induced fecal loss of BA by resin treatment reduces plasma cholesterol, presumably through induction of hepatic LDL receptors (LDLR). We here describe the effect of PR835, a drug belonging to a new class of lipid\u2010lowering agents that inhibit the Slc10a2 protein, the intestinal transporter responsible for active uptake of BA. Treatment reduced plasma cholesterol by 40% in mice devoid of both the LDLR and its ligand, apoE, while triglycerides and HDL cholesterol were unchanged. Cyp7a1 enzyme activity and mRNA were induced several\u2010fold, and hepatic HMG CoA reductase mRNA increased, mirroring an induced synthesis of BA and cholesterol. The addition of a statin potentiated the effect, leading to reductions of plasma total and LDL cholesterol by 64% and 70%, respectively. These effects could not be attributed to induction of other known hepatic lipoprotein receptors and indicate the presence of new points of targeting in lipid\u2010lowering therapy.<\/jats:p>","DOI":"10.1096\/fj.02-0341fje","type":"journal-article","created":{"date-parts":[[2003,1,28]],"date-time":"2003-01-28T17:25:55Z","timestamp":1043774755000},"page":"265-267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Pharmacological interference with intestinal bile acid transport reduces plasma cholesterol in LDL receptor\/apoE deficiency"],"prefix":"10.1096","volume":"17","author":[{"given":"Cecilia","family":"G\u00e4lman","sequence":"first","affiliation":[{"name":"Metabolism Unit Center for Metabolism and Endocrinology Department of Medicine Molecular Nutrition Unit Center for Nutrition and Toxicology NOVUM Karolinska Institute at Huddinge University Hospital Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann\u2010Margret","family":"\u00d6stlund\u2010Lindqvist","sequence":"additional","affiliation":[{"name":"Molecular Biology Cell Biology and Biochemistry Astra Zeneca R &amp; D M\u00f6lndal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Bj\u00f6rquist","sequence":"additional","affiliation":[{"name":"Molecular Biology Cell Biology and Biochemistry Astra Zeneca R &amp; D M\u00f6lndal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Schreyer","sequence":"additional","affiliation":[{"name":"Molecular Biology Cell Biology and Biochemistry Astra Zeneca R &amp; D M\u00f6lndal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lennart","family":"Svensson","sequence":"additional","affiliation":[{"name":"Molecular Biology Cell Biology and Biochemistry Astra Zeneca R &amp; D M\u00f6lndal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Angelin","sequence":"additional","affiliation":[{"name":"Metabolism Unit Center for Metabolism and Endocrinology Department of Medicine Molecular Nutrition Unit Center for Nutrition and Toxicology NOVUM Karolinska Institute at Huddinge University Hospital Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Rudling","sequence":"additional","affiliation":[{"name":"Metabolism Unit Center for Metabolism and Endocrinology Department of Medicine Molecular Nutrition Unit Center for Nutrition and Toxicology NOVUM Karolinska Institute at Huddinge University Hospital Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2002,12,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.97.15.1436"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1201-1282"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-199806000-00007"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-199906000-00009"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.9.3469"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.1.126"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0715com"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.10.4431"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2000.4600"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.36.25913"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(94)80066-9"},{"key":"e_1_2_6_13_1","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S0022-2275(20)38867-2","article-title":"Bile acid synthesis in man: assay of hepatic microsomal cholesterol 7 alpha\u2010hydroxylase activity by isotope dilution\u2010mass spectrometry","volume":"27","author":"Einarsson K.","year":"1986","journal-title":"J Lipid Res"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.15.6983"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65706-9"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00135a001"},{"key":"e_1_2_6_17_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/S0022-2275(20)30180-2","article-title":"BAREing it all. 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